Magnetic Resonance Imaging is a non-invasive modality that allows for deep-tissue imaging. Contrast agents decrease image acquisition time and increase the intrinsic contrast between different types of tissue. A new family of enzyme-activated contrast agents is emerging that has the ability to report on enzymatic processes in vivo. Towards this goal, five distinct approaches to modulate the relaxivity of gadolinium(III) chelates with peptides were investigated. The agents are proposed to undergo structural changes upon cleavage of a substrate peptide by a protease, ultimately resulting in a change in relaxivity. Contrast agents attached to the N-terminus of a peptide were used to study the effect of the N-terminal amino acid on the coordination geometry of a gadolinium(III) chelate. It was determined that the coordination geometry is independent of the identity of the N-terminal amino acid. A novel protection strategy was used to synthesize peptide-bridged macrobicyclic structures where a contrast agent is covalently attached to the side-chains of a peptide. The linker length of the macrobicyclic agents was varied in a systematic manner to study the effects of proximity of the peptide to the macrocycle in blocking inner-sphere water access. A self-immolative linkage was used between a DEVD peptide and a gadolinium(III) chelate to produce a contrast agent for the detection of caspase-3. The agent displays a decrease in relaxivity upon cleavage by caspase-3 due to a decreased water exchange rate for the cleaved chelate. The self-immolative agent displays high uptake with MDA-MB-231 cells. A coordinatively saturated gadolinium(III) complex, consisting of an amide-based chelate attached to the C-terminus of a peptide, provides a novel mechanism to restrict inner-sphere water access to gadolinium(III) chelates. The attachment of a small-molecule T1 contrast agent to a nanoparticle T2 contrast agent with a variable PEG spacer and a substrate peptide has the potential to provide a novel mechanism of relaxivity enhancement. The family of peptide-based contrast agents in the present work has the potential to enable MRI to detect proteases responsible for a variety of diseases. Each approach to modulate the relaxivity of gadolinium(III) chelates represents a paradigm for future studies of enzyme-activated MRI contrast agents.</.

Last modified

• 10/02/2018

Creator

• Bradley Douglas Ulrich

DOI

• https://doi.org/10.21985/N2245D

Subject

• Chemistry

Keyword

• Inorganic Chemistry

Date created

• 2008-12-03

Resource type

• Dissertation

Rights statement

• In Copyright